Calpains are a family of proteases that were scientifically recognized earlier than proteasomes and caspases, but remain enigmatic. However, they are known to participate in a multitude of physiological and pathological processes, performing 'limited proteolysis' whereby they do not destroy but rather modulate the functions of their substrates. Calpains are therefore referred to as 'modulator proteases'. Multidisciplinary research on calpains has begun to elucidate their involvement in pathophysiological mechanisms. Therapeutic strategies targeting malfunctions of calpains have been developed, driven primarily by improvements in the specificity and bioavailability of calpain inhibitors. Here, we review the calpain superfamily and calpain-related disorders, and discuss emerging calpain-targeted therapeutic strategies.